3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-hydroxy-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid (henceforth referred to as T-5224) has an excellent antiarthritic action and has an osteoclastic suppressing action, furthermore, it is very safe, has excellent pharmacokinetics and is valuable as an antirheumatic agent (Non-patent document 1).
T-5224 is prepared by deprotecting 3-{5-[4-(cyclopentyloxy)-2-hydroxybenzoyl]-2-[(3-oxo-2-substituted-2,3-dihydro-1,2-benzisoxazol-6-yl)methoxy]phenyl}propionic acid ester (henceforth, referred to as T-5224 intermediate) (Patent document 1).
The T-5224 intermediate is prepared by reacting 6-(bromomethyl)-2-(methoxymethyl)-1,2-benzisoxazol-3(2H)-one (henceforth referred to as preparation intermediate 1-1) or 6-(bromomethyl)-3-(methoxymethoxy)-1,2-benzisoxazole (henceforth referred to as preparation intermediate 1-2) with 3-{5-[4-cyclopentyloxy)-2-hydroxybenzoyl]-2-hydroxyphenyl}propionic acid methyl ester (henceforth referred to as preparation intermediate 2) (Patent document 1).
However, preparation intermediate 1-1 and preparation intermediate 1-2 both have drawbacks such as that they both (a) are oil substances and (b) have low purity and stability.
The preparation methods for the preparation intermediate 1-1 and preparation intermediate 1-2 both have drawbacks such as that they (c) require complex procedures such as silica gel column chromatography, (d) have low yield and (e) use raw materials which are dangerous and have a high toxicity (chloromethyl methyl ether).
The preparation method for preparation intermediate 2 has drawbacks such as that it (f) requires complicated procedures such as distillation and column chromatography and (g) uses extremely expensive, flammable and self-reactive reagents (azodicarbonyl compounds such as diethyl azodicarboxylate and diisopropyl azodicarboxylate), and (h) a large amount of aluminum chloride waste solution which requires complex treatments is generated.
By reacting preparation intermediate 1-1 or preparation intermediate 1-2 with preparation intermediate 2, the T-5224 intermediates that are prepared have drawbacks such as that they are all (i) oil substances, (j) and for isolating these, complex procedures such as silica gel column chromatography are required.
Using preparation intermediate 1-1, preparation intermediate 1-2, and preparation intermediate 2, the method for preparing T-5224 intermediate is not satisfactory.
Intermediate product 2 can be prepared from 2-oxo-2H-chromene carboxylic acid or a salt thereof. Examples of the preparation method of 2-oxo-2H-chromene carboxylic acid or a salt thereof include, for example, (A) a method in which after brominating 6-methyl-2H-chromen-2-one and reacting with hexamethylenetetramine, hydrolysis and oxidation are conducted (Patent document 2); (B) a method of ring-closing a cinnamic acid ester which is obtained by several processes from p-hydroxybenzoic acid or an ester thereof (Non-patent document 2); (C) a method for ring-closing of p-hydroxybenzoic acid or an ester thereof (Non-patent document 3); (D) a method in which after conducting Knoevenagel condensation of 3-formyl-4-hydroxybenzoic acid and maleic acid, heating and decarboxylating are conducted (Non-patent document 4).
However, the preparation method (A) has drawbacks such as that it (k) requires complex procedures, (l) there are many types of reagents and they are expensive.
The preparation method (B) has drawbacks such as that (m) the ring-closing reaction is at high temperatures, (n) there are many steps, and (O) there are many types of reagents and they are expensive.
Preparation method (C) has drawbacks such as that (p) it has low yield.
Preparation method (D) has drawbacks such as that (q) the starting substance is expensive and (r) the decarboxylating reaction is at high temperatures.
Methods for industrial preparation of 2-oxo-2H-chromene carboxylic acid or a salt thereof have not been satisfactory.    Patent document 1: International publication WO03/042150 pamphlet    Patent document 2: International publication WO2004/050082 pamphlet    Non-patent document 1: Arthritis Rheum, 2006 Vol. 54 (9), S232    Non-patent document 2: Chem. Pharm. Bull., 1994, Vol. 42, p. 2170-2173    Non-patent document 3: J. Org. Chem. 1951, Vol. 16, p. 253-261.    Non-patent document 4: Annali di Chimica (Rome) 1966 Vol. 56 (6), p. 700-716
There is a strong desire for a preparation method that can easily mass-prepare T-5224 using inexpensive raw materials and that is safe for human bodies and does not have a large environmental impact.